GCN5 modulates osteogenic differentiation of periodontal ligament stem cells through DKK1 acetylation in inflammatory microenvironment.
GCN5 modulates osteogenic differentiation of periodontal ligament stem cells through DKK1 acetylation in inflammatory microenvironment.
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GCN5通过炎症微环境中DKK1乙酰化调节牙周膜干细胞的成骨分化
DOI：
10.1038/srep26542
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发表时间：
2016-05-24
影响因子：
4.6
通讯作者：
Jin Y
中科院分区：
文献类型：
--
作者：
Li B;Sun J;Dong Z;Xue P;He X;Liao L;Yuan L;Jin Y
牙周炎患者牙周膜干细胞（PDLSCs）成骨分化缺陷。然而，炎症微环境中PDLSC成骨分化受损的机制仍不清楚。在这项研究中，我们发现微环境中的炎症导致组蛋白乙酰转移酶GCN 5表达下调，GCN 5的缺乏导致PDLSC的成骨分化降低。前期研究表明PDLSCs的Wnt/β-cateinin通路激活导致成骨分化缺陷。我们发现GCN 5基因敲低可降低Wnt/β-cateinin通路抑制剂DKK 1的表达，从而激活PDLSCs的Wnt/β-cateinin通路。在机制上，GCN 5通过组蛋白H3赖氨酸9（H3 K9）和组蛋白H3赖氨酸14（H3 K14）在其启动子区的乙酰化来调节DKK 1表达。有趣的是，我们发现体内注射阿司匹林通过抑制炎症和上调GCN 5表达来挽救大鼠牙周炎。此外，阿司匹林治疗PDLSC上调GCN 5表达并增加PDLSC的成骨分化。结论：GCN 5可能通过DKK 1的乙酰化修饰发挥牙周炎的保护作用，以GCN 5为靶点的药物如阿司匹林可能成为治疗牙周炎的新途径。
Periodontal ligament stem cells (PDLSCs) from periodontitis patients showed defective osteogenic differentiation. However, the mechanism of impaired osteogenic differentiation of PDLSCs in inflammatory microenvironments is still unclear. In this study, we found that inflammation in the microenvironment resulted in downregulation of histone acetyltransferase GCN5 expression and lack of GCN5 caused decreased osteogenic differentiation of PDLSCs. Previous study showed activated Wnt/β-cateinin pathway of PDLSCs resulted in defective osteogenic differentiation. Here we found knockdown of GCN5 decreased the expression of DKK1, an inhibitor of Wnt/β-cateinin pathway, thus activated Wnt/β-catenin pathway of PDLSCs. Mechanistically, GCN5 regulated DKK1 expression by acetylation of Histone H3 lysine 9 (H3K9) and Histone H3 lysine 14 (H3K14) at its promoter region. Interestingly, we found thatin vivoinjection of aspirin rescued the periodontitis of rats through inhibiting inflammation and upregulating GCN5 expression. Furthermore, aspirin treatment of PDLSCs upregulated GCN5 expression and increased osteogenic differentiation of PDLSCs. In conclusion, GCN5 plays a protective role in periodontitis through acetylation of DKK1 and applying drugs targeting GCN5, such as aspirin, could be a new approach for periodontitis treatment.